To investigate the role of the P2X7 receptor in learning and memory dysfunction induced by HIV-1 envelope glycoprotein gp120 (gp120), we established HIV-1-associated dementia (HAD) animal models by intracerebroventricular (ICV) infusion of gp120 in rats. We observed gp120-induced cognitive dysfunction in the radial arm water maze test. Results showed that rats in the gp120 groups had longer escape latencies and more errors compared to those in the control group. For example, the average trial time in the 50-ng/day-gp120 group on day eight (16.57 ± 1.71 s, N = 90) was significantly longer than that of control rats (9.93 ± 0.68 s, N = 90). The relative expression of P2X7 mRNA in the control, 50-, 70-, and 100-ng/day-gp120 groups were 0.43 ± 0.06, 0.48 ± 0.07, 0.83 ± 0.05, and 0.84 ± 0.10, respectively; relative P2X7 protein expression in those groups was 0.63 ± 0.07, 1.08 ± 0.06, 0.90 ± 0.07, and 1.03 ± 0.11, respectively. According to immunohistochemistry analysis, the staining intensity values for P2X7 protein expression in the control, 50-, 70-, and 100-ng/d-gp120 groups were 0.88 ± 0.07, 1.41 ± 0.12, 1.28 ± 0.13, and 1.31 ± 0.10, respectively. The above results showed that the expression of P2X7 increased significantly in the hippocampus of gp120 rats compared to that of the control group. These results suggest that ICV infusion of gp120 can successfully mimic HAD in rats, and P2X7 may be involved in gp120-induced cognitive dysfunction. This could provide a theoretical foundation and potential drug target for research and treatment of ADC.